tRNA therapeutics for genetic diseases

Coller, Jeff; Ignatova, Zoya

doi:10.1038/s41573-023-00829-9

Cited by 18 publications

(13 citation statements)

References 233 publications

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“…Considering the relevant impact of the individual complex molecular context on readthrough success, the future direction of the present research will be to design a personalised induced-readthrough strategy. This, by selecting low-toxic novel classes of nonsense suppressor drugs (e.g., ELX-02 and PTI-428) and/or molecules as guanidino quinazolines and pyrimidines scaffolds [53,67,68], together with tRNAs and antisense oligonucleotides, provide a selective tropism towards a desired cell or tissue [69,70].…”

Section: Discussionmentioning

confidence: 99%

Gene Dosage of F5 c.3481C>T Stop-Codon (p.R1161Ter) Switches the Clinical Phenotype from Severe Thrombosis to Recurrent Haemorrhage: Novel Hypotheses for Readthrough Strategy

Gemmati,

D’Aversa,

Antonica

et al. 2024

Genes

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Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe–moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules.

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Section: Discussionmentioning

confidence: 99%

Gene Dosage of F5 c.3481C>T Stop-Codon (p.R1161Ter) Switches the Clinical Phenotype from Severe Thrombosis to Recurrent Haemorrhage: Novel Hypotheses for Readthrough Strategy

Gemmati,

D’Aversa,

Antonica

et al. 2024

Genes

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“…Sup-tRNAs represent a transformative pharmacological opportunity to treat human genetic diseases. The prospect of therapeutic sup-tRNAs requires a better understanding of the mechanism of PTC translation, how synthetic tRNAs are metabolized, and delivery strategies (Coller and Ignatova, 2024). In the context of PTC translation, developing potent sup-tRNAs is critical and remains a fundamental area of research.…”

Section: Discussionmentioning

confidence: 99%

“…Very few treatment options are available for patients suffering from PTC-related conditions. In recent years, suppressor tRNAs (sup-tRNAs) have regained notoriety as a promising therapeutic approach based on their ability to translate PTCs and restore protein synthesis (Porter et al, 2021;Dolgin, 2022;Lin and Glatt, 2022;Anastassiadis and Köhrer, 2023;Coller and Ignatova, 2024). The reinvigorated interest in sup-tRNAs is supported by exciting new evidence demonstrating their efficacy and safety in mouse models together with available RNA delivery strategies (e.g., lipid nanoparticles and adeno-associated virus) (Lueck et al, 2019;Wang et al, 2022;Albers et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Suppressor tRNAs at the interface of genetic code expansion and medicine

Awawdeh,

Radecki,

Vargas-Rodriguez

2024

Front. Genet.

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Suppressor transfer RNAs (sup-tRNAs) are receiving renewed attention for their promising therapeutic properties in treating genetic diseases caused by nonsense mutations. Traditionally, sup-tRNAs have been created by replacing the anticodon sequence of native tRNAs with a suppressor sequence. However, due to their complex interactome, considering other structural and functional tRNA features for design and engineering can yield more effective sup-tRNA therapies. For over 2 decades, the field of genetic code expansion (GCE) has created a wealth of knowledge, resources, and tools to engineer sup-tRNAs. In this Mini Review, we aim to shed light on how existing knowledge and strategies to develop sup-tRNAs for GCE can be adopted to accelerate the discovery of efficient and specific sup-tRNAs for medical treatment options. We highlight methods and milestones and discuss how these approaches may enlighten the research and development of tRNA medicines.

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“…Our review focuses on the emerging field of tRNA medicine, which has the goal of using cognate, nonsense, and missense suppressor tRNAs to correct or ameliorate genetic defects that cause disease in humans. , The findings noted in Section support the idea that suppressor tRNAs, perhaps even those inspired by natural variants, will represent viable routes to tRNA medicine. The potential for tRNA therapeutics was first demonstrated in 1979 with a stop-codon suppressor of a beta-thalassemia gene .…”

Section: Introductionmentioning

confidence: 99%

“…The potential for tRNA therapeutics was first demonstrated in 1979 with a stop-codon suppressor of a beta-thalassemia gene . Although other applications have been reported since that time, the field of tRNA therapeutics was held back because of concerns related to gene therapies as well as deep skepticism of RNA-based medicines. , The major success of mRNA-based vaccines that provided immunizations for Coronavirus disease 2019 (COVID-19) reignited interest in RNA-based therapeutics, including tRNA medicines. Our review highlights recent advances that have demonstrated tRNA-based medicines, either as synthetic RNAs or as tRNA genes, can treat human diseases in cells and clinically relevant model systems.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and Delivery of tRNA Therapeutics

Ward,

Beharry,

Tennakoon

et al. 2024

Chem. Rev.

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Transfer ribonucleic acid (tRNA) therapeutics will provide personalized and mutation specific medicines to treat human genetic diseases for which no cures currently exist. The tRNAs are a family of adaptor molecules that interpret the nucleic acid sequences in our genes into the amino acid sequences of proteins that dictate cell function. Humans encode more than 600 tRNA genes. Interestingly, even healthy individuals contain some mutant tRNAs that make mistakes. Missense suppressor tRNAs insert the wrong amino acid in proteins, and nonsense suppressor tRNAs read through premature stop signals to generate full length proteins. Mutations that underlie many human diseases, including neurodegenerative diseases, cancers, and diverse rare genetic disorders, result from missense or nonsense mutations. Thus, specific tRNA variants can be strategically deployed as therapeutic agents to correct genetic defects. We review the mechanisms of tRNA therapeutic activity, the nature of the therapeutic window for nonsense and missense suppression as well as wild-type tRNA supplementation. We discuss the challenges and promises of delivering tRNAs as synthetic RNAs or as gene therapies. Together, tRNA medicines will provide novel treatments for common and rare genetic diseases in humans. CONTENTS

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tRNA therapeutics for genetic diseases

Cited by 18 publications

References 233 publications

Gene Dosage of F5 c.3481C>T Stop-Codon (p.R1161Ter) Switches the Clinical Phenotype from Severe Thrombosis to Recurrent Haemorrhage: Novel Hypotheses for Readthrough Strategy

Gene Dosage of F5 c.3481C>T Stop-Codon (p.R1161Ter) Switches the Clinical Phenotype from Severe Thrombosis to Recurrent Haemorrhage: Novel Hypotheses for Readthrough Strategy

Suppressor tRNAs at the interface of genetic code expansion and medicine

Mechanisms and Delivery of tRNA Therapeutics

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